US7074782B2ExpiredUtilityPatentIndex 84
Carbamate caspase inhibitors and uses thereof
Est. expiryMar 29, 2020(expired)· nominal 20-yr term from priority
A61P 43/00A61P 3/10A61P 37/04A61P 9/10A61P 7/04A61P 37/06A61P 9/00A61P 7/06A61P 37/02A61P 25/32A61P 31/20A61P 25/08A61P 25/28A61P 31/12A61P 25/16A61P 31/06A61P 25/30A61P 31/14A61P 35/02A61P 27/00A61P 31/04A61P 25/14A61P 35/00A61P 29/00A61P 31/18A61P 19/00C07D 223/26A61P 13/12C07D 279/30A61P 1/04C07D 223/28C07D 209/08C07D 209/86A61P 19/04A61P 19/10C07D 403/12A61P 17/14A61P 19/08A61P 1/16A61P 11/06A61P 19/02A61P 21/00C07D 221/12A61P 1/18A61K 31/55
84
PatentIndex Score
15
Cited by
19
References
45
Claims
Abstract
This invention provides caspase inhibitors of formula I: wherein Z is oxygen or sulfur; R 1 is hydrogen, —CHN 2 , R, CH 2 OR, CH 2 SR, or —CH 2 Y; Y is an electronegative leaving group; R 2 is CO 2 H, CH 2 CO 2 H, or esters, amides or isosteres thereof; R 3 is a group capable of fitting into the S2 subsite of a caspase enzyme; R 4 and R 5 are taken together with the intervening nitrogen to form heterocyclic ring and R is as described in the specification. The compounds are effective inhibitors of apoptosis and IL-1β secretion.
Claims
exact text as granted — not AI-modified1. A compound of formula I:
wherein:
Z is oxygen or sulfur;
R 1 is hydrogen, —CHN 2 , —R, —CH 2 OR, —CH 2 SR, or —CH 2 Y;
R is a C 1-12 aliphatic, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl ring, wherein each of these groups is optionally substituted, and wherein said heterocyclic ring is a three to nine membered saturated or unsaturated mono-, bi-, or tri-heterocyclic ring system wherein each ring contains up to three heteroatoms selected from O, N, or S;
Y is an electronegative leaving group selected from F, Cl, Br, I, arylsulfonyloxy, alkylsulfonyloxy, trifluoromethanesulfonyloxy, OR′, SR′, —OC═O(R′), or —OPO(R 6 ) (R 7 );
wherein R′ is an aliphatic group, an aryl group, an aralkyl group, a carbocyclic group, an alkyl carbocyclic group, a heterocyclic group, or an alkyl heterocyclic group;
wherein R 6 and R 7 are independently selected from R or OR;
R 2 is CO 2 H, CH 2 CO 2 H or C 1-6 alkyl esters, C 3-10 cycloalkyl esters, or cholesterol esters thereof; or primary, secondary or tertiary amides thereof; wherein suitable substituents on the nitrogen of said amides includes one or more C 1-6 alkyl groups optionally substituted with N(R) 2 or 5–6 membered heterocyclic rings containing 1–2 heteroatoms; and
wherein R is linear or branched C 1-12 aliphatic;
R 3 is selected from H, a side chain of a natural α-amino acid, or a substituted or unsubstituted group having a molecular weight up to about 140 Daltons selected from aliphatic, aryl, aralkyl, heterocyclyl or heterocyclylalkyl ring wherein said heterocyclyl or heterocyclylalkyl ring is a three to nine membered saturated or unsaturated mono-, bi-, or tri-heterocyclic ring system wherein each ring contains up to three heteroatoms selected from O, N, or S; and
R 4 and R 5 taken together with the intervening nitrogen form a mono-, bi- or tricyclic hetero ring system having 1–6 heteroatoms selected from nitrogen, oxygen or sulfur;
wherein said ring system is optionally substituted with one or more groups independently selected from halogen, —R 9 , —OR 9 , —OH, —SH, —SR 9 , protected OH (such as acyloxy), phenyl (Ph), substituted Ph, —OPh, substituted —OPh, —NO 2 , —CN, —NH 2 , —NHR 9 , —N(R 9 ) 2 , —NHCOR 9 , —NHCONHR 9 , —NHCON(R 9 ) 2 , —NR 9 COR 9 , —NHCO 2 R 9 , —CO 2 R 9 , —CO 2 H, —COR 9 , —CONHR 9 , —CON(R 9 ) 2 , —S(O) 2 R 9 , —SONH 2 , —S(O)R 9 , —SO 2 NHR 9 , or —NHS(O) 2 R 9 ;
wherein each R 9 is independently selected from an
aliphatic group or a substituted aliphatic group;
wherein the optional substituents on said C 1-12 aliphatic group or aryl, aralkyl, heterocyclyl, or heterocyclylalkyl ring is independently selected from, from halogen, —R 11 , —OR 11 , —OH, —SH, —SR 11 , acyloxy, substituted or unsubstituted Ph or OPh, —NO 2 , —CN, —NH 2 , —NHR 11 , —N(R 11 ) 2 , —NHCOR 11 , —NHCONHR 11 , —NHCON(R 11 ) 2 , —NR 11 COR 11 , —NHCO 2 R 11 , —CO 2 R 11 , —CO 2 H, —COR 11 , —CONHR 11 , —CON(R 11 ) 2 , —S(O) 2 R 11 , —SONH 2 , —S(O)R 11 , —SO 2 NHR 11 , —NHS(O) 2 R 11 , ═O, ═S, ═NNHR 11 , ═NNR 11 , ═N—OR 11 , ═NNHCOR 11 , ═NNHCO 2 R 11 , ═NNHSO 2 R 11 , or ═NR 11 ; and
wherein each R 11 is independently selected from a C 1-12 aliphatic group or a substituted C 1-12 aliphatic group.
2. The compound of claim 1 wherein the compound is selected from those compounds listed in Table 1 below:
No.
Structure
12
13
14
15
16
17
18
19
38
39
40
41
42
43
44
45
46
47
48
3. The compound of claim 1 wherein the compound is selected from the following:
4. The compound according to claim 1 wherein Z is oxygen.
5. The compound according to claim 1 wherein R 1 is hydrogen, —R, —CH 2 OR, —CH 2 SR, or —CH 2 Y.
6. The compound according to claim 1 wherein R 2 is CO 2 H, or C 1-6 alkyl esters, C 3-10 cycloalkyl esters, or cholesterol esters thereof; or primary, secondary or tertiary amides thereof; wherein suitable substituents on the nitrogen of said amides includes one or more C 1-6 alkyl groups optionally substituted with N(R) 2 or 5–6 membered heterocyclic rings containing 1–2 heteroatoms; and wherein R is linear or branched C 1-12 aliphatic.
7. The compound according to claim 1 wherein R 3 is a group having a molecular weight up to 140 Daltons selected from aliphatic, aryl, aralkyl, heterocyclyl or heterocyclylalkyl ring wherein said heterocyclyl ring is a three to nine membered saturated or unsaturated mono-, bi-, or tri-heterocyclic ring system wherein each ring contains up to three heteroatoms selected from O, N, or S.
8. The compound according to claim 1 wherein R 4 and R 5 taken together with the intervening nitrogen form a mono-, bi- or tricyclic hetero ring system wherein each ring of the system has 5–7 ring atoms;
wherein said ring system is optionally substituted with one or more groups independently selected from halogen, —R 9 , —OR 9 , —OH, —SH, —SR 9 , protected OH (such as acyloxy), phenyl (Ph), substituted Ph, —OPh, substituted —OPh, —NO 2 , —CN, —NH 2 , —NHR 9 , —N(R 9 ) 2 , —NHCOR 9 , —NHCONHR 9 , —NHCON(R 9 ) 2 , —NR 9 COR 9 , —NHCO 2 R 9 , —CO 2 R 9 , —CO 2 H, —COR 9 , —CONHR 9 , —CON(R 9 ) 2 , —S(O) 2 R 9 , —SONH 2 , —S(O)R 9 , —SO 2 NHR 9 , or —NHS(O) 2 R 9 ; and
wherein each R 9 is independently selected from an aliphatic group or a substituted aliphatic group.
9. The compound according to claim 1 wherein Z is oxygen; and
wherein R 1 is hydrogen, —R, —CH 2 OR, —CH 2 SR, or —CH 2 Y.
10. The compound according to claim 1 wherein Z is oxygen; and
wherein R 2 is CO 2 H, CH 2 CO 2 H or C 1-6 alkyl esters, C 3-10 cycloalkyl esters, or cholesterol esters thereof; or primary, secondary or tertiary amides thereof; wherein suitable substituents on the nitrogen of said amides includes one or more C 1-6 alkyl groups optionally substituted with N(R) 2 or 5–6 membered heterocyclic rings containing 1–2 heteroatoms; and wherein R is linear or branched C 1-12 aliphatic.
11. The compound according to claim 1 wherein Z is oxygen; and
wherein R 3 is a group having a molecular weight up to 140 Daltons selected from aliphatic, aryl, aralkyl, heterocyclyl or heterocyclylalkyl ring wherein said heterocyclyl ring is a three to nine membered saturated or unsaturated mono-, bi-, or tri-heterocyclic ring system wherein each ring contains up to three heteroatoms selected from O, N, or S.
12. The compound according to claim 1 wherein Z is oxygen; and
wherein R 4 and R 5 taken together with the intervening nitrogen form a mono-, bi- or tricyclic hetero ring system wherein each ring of the system has 5–7 ring atoms;
wherein said ring system is optionally substituted with one or more groups independently selected from halogen, —R 9 , —OR 9 , —OH, —SH, —SR 9 , protected OH (such as acyloxy), phenyl (Ph), substituted Ph, —OPh, substituted —OPh, —NO 2 , —CN, —NH 2 , —NHR 9 , —N(R 9 ) 2 , —NHCOR 9 , —NHCONHR 9 , —NHCON(R 9 ) 2 , —NR 9 COR 9 , —NHCO 2 R 9 , —CO 2 R 9 , —CO 2 H, —COR 9 , —CONHR 9 , —CON(R 9 ) 2 , —S(O) 2 R 9 , —SONH 2 , —S(O)R 9 , —SO 2 NHR 9 , or —NHS(O) 2 R 9 ; and
wherein each R 9 is independently selected from an aliphatic group or a substituted aliphatic group.
13. The compound according to claim 1 wherein R 1 is hydrogen, —R, —CH 2 OR, —CH 2 SR, or —CH 2 Y; and
wherein R 2 is CO 2 H, CH 2 CO 2 H or C 1-6 alkyl esters, C 3-10 cycloalkyl esters, or cholesterol esters thereof; or primary, secondary or tertiary amides thereof; wherein suitable substituents on the nitrogen of said amides includes one or more C 1-6 alkyl groups optionally substituted with N(R) 2 or 5–6 membered heterocyclic rings containing 1–2 heteroatoms; and wherein R is linear or branched C 1-12 aliphatic.
14. The compound according to claim 1 wherein R 1 is hydrogen, —R, —CH 2 OR, —CH 2 SR, or —CH 2 Y; and wherein R 3 is a group having a molecular weight up to 140 Daltons selected from aliphatic, aryl, aralkyl, heterocyclyl or heterocyclylalkyl ring wherein said heterocyclyl ring is a three to nine membered saturated or unsaturated mono-, bi-, or tri-heterocyclic ring system wherein each ring contains up to three heteroatoms selected from O, N, or S.
15. The compound according to claim 1 wherein R 1 is hydrogen, —R, —CH 2 OR, —CH 2 SR, or —CH 2 Y; and wherein R 4 and R 5 taken together with the intervening nitrogen form a mono-, bi- or tricyclic hetero ring system wherein each ring of the system has 5–7 ring atoms;
wherein said ring system is optionally substituted with one or more groups independently selected from halogen, —R 9 , —OR 9 , —OH, —SH, —SR 9 , protected OH (such as acyloxy), phenyl (Ph), substituted Ph, —OPh, substituted —OPh, —NO 2 , —CN, —NH 2 , —NHR 9 , —N(R 9 ) 2 , —NHCOR 9 , —NHCONHR 9 , —NHCON(R 9 ) 2 , —NR 9 COR 9 , —NHCO 2 R 9 , —CO 2 R 9 , —CO 2 H, —COR 9 , —CONHR 9 , —CON(R 9 ) 2 , —S(O) 2 R 9 , —SONH 2 , —S(O)R 9 , —SO 2 NHR 9 , or —NHS(O) 2 R 9 ; and
wherein each R 9 is independently selected from an aliphatic group or a substituted aliphatic group.
16. The compound according to claim 1 wherein R 2 is:
CO 2 H, CH 2 CO 2 H or C 1-6 alkyl esters, C 3-10 cycloalkyl esters, or cholesterol esters thereof; or primary, secondary or tertiary amides thereof; wherein suitable substituents on the nitrogen of said amides includes one or more C 1-6 alkyl groups optionally substituted with N(R) 2 or 5–6 membered heterocyclic rings containing 1–2 heteroatoms; and wherein R is linear or branched C 1-12 aliphatic; and
wherein R 3 is a group having a molecular weight up to 140 Daltons selected from aliphatic, aryl, aralkyl, heterocyclyl or heterocyclylalkyl ring wherein said heterocyclyl ring is a three to nine membered saturated or unsaturated mono-, bi-, or tri-heterocyclic ring system wherein each ring contains up to three heteroatoms selected from O, N, or S.
17. The compound according to claim 1 wherein R 2 is:
CO 2 H, CH 2 CO 2 H or C 1-6 alkyl esters, C 3-10 cycloalkyl esters, or cholesterol esters thereof; or primary, secondary or tertiary amides thereof; wherein suitable substituents on the nitrogen of said amides includes one or more C 1-6 alkyl groups optionally substituted with N(R) 2 or 5–6 membered heterocyclic rings containing 1–2 heteroatoms; and wherein R is linear or branched C 1-12 aliphatic; and
wherein R 4 and R 5 taken together with the intervening nitrogen form a mono-, bi- or tricyclic hetero ring system wherein each ring of the system has 5–7 ring atoms;
wherein said ring system is optionally substituted with one or more groups independently selected from halogen, —R 9 , —OR 9 , —OH, —SH, —SR 9 , protected OH (such as acyloxy), phenyl (Ph), substituted Ph, —OPh, substituted —OPh, —NO 2 , —CN, —NH 2 , —NHR 9 , —N(R 9 ) 2 , —NHCOR 9 , —NHCONHR 9 , —NHCON(R 9 ) 2 , —NR 9 COR 9 , —NHCO 2 R 9 , —CO 2 R 9 , —CO 2 H, —COR 9 , —CONHR 9 , —CON(R 9 ) 2 , —S(O) 2 R 9 , —SONH 2 , —S(O)R 9 , —SO 2 NHR 9 , or —NHS(O) 2 R 9 ; and
wherein each R 9 is independently selected from an aliphatic group or a substituted aliphatic group.
18. The compound according to claim 1 wherein R 3 is a group having a molecular weight up to 140 Daltons selected from aliphatic, aryl, aralkyl, heterocyclyl or heterocyclylalkyl ring wherein said heterocyclyl ring is a three to nine membered saturated or unsaturated mono-, bi-, or tri-heterocyclic ring system wherein each ring contains up to three heteroatoms selected from O, N, or S; and
wherein R 4 and R 5 taken together with the intervening nitrogen form a mono-, bi- or tricyclic hetero ring system wherein each ring of the system has 5–7 ring atoms;
wherein said ring system is optionally substituted with one or more groups independently selected from halogen, —R 9 , —OR 9 , —OH, —SH, —SR 9 , protected OH (such as acyloxy), phenyl (Ph), substituted Ph, —OPh, substituted —OPh, —NO 2 , —CN, —NH 2 , —NHR 9 , —N(R 9 ) 2 , —NHCOR 9 , —NHCONHR 9 , —NHCON(R 9 ) 2 , —NR 9 COR 9 , —NHCO 2 R 9 , —CO 2 R 9 , —CO 2 H, —COR 9 , —CONHR 9 , —CON(R 9 ) 2 , —S(O) 2 R 9 , —SONH 2 , —S(O)R 9 , —SO 2 NHR 9 , or —NHS(O) 2 R 9 ; and
wherein each R 9 is independently selected from an aliphatic group or a substituted aliphatic group.
19. The compound according to claim 1 wherein Z is oxygen;
wherein R 1 is hydrogen, —R, —CH 2 OR, —CH 2 SR, or —CH 2 Y; and
wherein R 2 is:
CO 2 H, CH 2 CO 2 H or C 1-6 alkyl esters, C 3-10 cycloalkyl esters, or cholesterol esters thereof; or primary, secondary or tertiary amides thereof; wherein suitable substituents on the nitrogen of said amides includes one or more C 1-6 alkyl groups optionally substituted with N(R) 2 or 5–6 membered heterocyclic rings containing 1–2 heteroatoms; and wherein R is linear or branched C 1-12 aliphatic.
20. The compound according to claim 1 wherein Z is oxygen;
wherein R 1 is hydrogen, —R, —CH 2 OR, —CH 2 SR, or —CH 2 Y; and
wherein R 3 is a group having a molecular weight up to 140 Daltons selected from aliphatic, aryl, aralkyl, heterocyclyl or heterocyclylalkyl ring wherein said heterocyclyl ring is a three to nine membered saturated or unsaturated mono-, bi-, or tri-heterocyclic ring system wherein each ring contains up to three heteroatoms selected from O, N, or S.
21. The compound according to claim 1 wherein Z is oxygen;
wherein R 1 is hydrogen, —R, —CH 2 OR, —CH 2 SR, or —CH 2 Y; and
wherein R 4 and R 5 taken together with the intervening nitrogen form a mono-, bi- or tricyclic hetero ring system wherein each ring of the system has 5–7 ring atoms;
wherein said ring system is optionally substituted with one or more groups independently selected from halogen, —R 9 , —OR 9 , —OH, —SH, —SR 9 , protected OH (such as acyloxy), phenyl (Ph), substituted Ph, —OPh, substituted —OPh, —NO 2 , —CN, —NH 2 , —NHR 9 , —N(R 9 ) 2 , —NHCOR 9 , —NHCONHR 9 , —NHCON(R 9 ) 2 , —NR 9 COR 9 , —NHCO 2 R 9 , —CO 2 R 9 , —CO 2 H, —COR 9 , —CONHR 9 , —CON(R 9 ) 2 , —S(O) 2 R 9 , —SONH 2 , —S(O)R 9 , —SO 2 NHR 9 , or —NHS(O) 2 R 9 ; and
wherein each R 9 is independently selected from an aliphatic group or a substituted aliphatic group.
22. The compound according to claim 1 wherein R 1 is hydrogen, —R, —CH 2 OR, —CH 2 SR, or —CH 2 Y;
wherein R 2 is:
CO 2 H, CH 2 CO 2 H or C 1-6 alkyl esters, C 3-10 cycloalkyl esters, or cholesterol esters thereof; or primary, secondary or tertiary amides thereof; wherein suitable substituents on the nitrogen of said amides includes one or more C 1-6 alkyl groups optionally substituted with N(R) 2 or 5–6 membered heterocyclic rings containing 1–2 heteroatoms; and wherein R is linear or branched C 1-12 aliphatic;
wherein R 3 is a group having a molecular weight up to 140 Daltons selected from aliphatic, aryl, aralkyl, heterocyclyl or heterocyclylalkyl ring wherein said heterocyclyl ring is a three to nine membered saturated or unsaturated mono-, bi-, or tri-heterocyclic ring system wherein each ring contains up to three heteroatoms selected from O, N, or S.
23. The compound according to claim 1 wherein R 1 is hydrogen, —R, —CH 2 OR, —CH 2 SR, or —CH 2 Y;
wherein R 2 is:
CO 2 H, CH 2 CO 2 H or C 1-6 alkyl esters, C 3-10 cycloalkyl esters, or cholesterol esters thereof; or primary, secondary or tertiary amides thereof; wherein suitable substituents on the nitrogen of said amides includes one or more C 1-6 alkyl groups optionally substituted with N(R) 2 or 5–6 membered heterocyclic rings containing 1–2 heteroatoms; and wherein R is linear or branched C 1-12 aliphatic; and
wherein R 4 and R 5 taken together with the intervening nitrogen form a mono-, bi- or tricyclic hetero ring system wherein each ring of the system has 5–7 ring atoms;
wherein said ring system is optionally substituted with one or more groups independently selected from halogen, —R 9 , —OR 9 , —OH, —SH, —SR 9 , protected OH (such as acyloxy), phenyl (Ph), substituted Ph, —OPh, substituted —OPh, —NO 2 , —CN, —NH 2 , —NHR 9 , —N(R 9 ) 2 , —NHCOR 9 , —NHCONHR 9 , —NHCON(R 9 ) 2 , —NR 9 COR 9 , —NHCO 2 R 9 , —CO 2 R 9 , CO 2 H, —COR 9 , —CONHR 9 , —CON(R 9 ) 2 , —S(O) 2 R 9 , —SONH 2 , —S(O)R 9 , —SO 2 NHR 9 , or —NHS(O) 2 R 9 ; and
wherein each R 9 is independently selected from an aliphatic group or a substituted aliphatic group.
24. The compound according to claim 1 wherein R 1 is hydrogen, —R, —CH 2 OR, —CH 2 SR, or —CH 2 Y;
wherein R 3 is a group having a molecular weight up to 140 Daltons selected from aliphatic, aryl, aralkyl, heterocyclyl or heterocyclylalkyl ring wherein said heterocyclyl ring is a three to nine membered saturated or unsaturated mono-, bi-, or tri-heterocyclic ring system wherein each ring contains up to three heteroatoms selected from O, N, or S; and
wherein R 4 and R 5 taken together with the intervening nitrogen form a mono-, bi- or tricyclic hetero ring system wherein each ring of the system has 5–7 ring atoms;
wherein said ring system is optionally substituted with one or more groups independently selected from halogen, —R 9 , —OR 9 , —OH, —SH, —SR 9 , protected OH (such as acyloxy), phenyl (Ph), substituted Ph, —OPh, substituted —OPh, —NO 2 , —CN, —NH 2 , —NHR 9 , —N(R 9 ) 2 , —NHCOR 9 , —NHCONHR 9 , —NHCON(R 9 ) 2 , —NR 9 COR 9 , —NHCO 2 R 9 , —CO 2 R 9 , CO 2 H, —COR 9 , —CONHR 9 , —CON(R 9 ) 2 , —S(O) 2 R 9 , —SONH 2 , —S(O)R 9 , —SO 2 NHR 9 , or —NHS(O) 2 R 9 ; and
wherein each R 9 is independently selected from an aliphatic group or a substituted aliphatic group.
25. The compound according to claim 1 wherein R 2 is:
CO 2 H, CH 2 CO 2 H or C 1-6 alkyl esters, C 3-10 cycloalkyl esters, or cholesterol esters thereof; or primary, secondary or tertiary amides thereof; wherein suitable substituents on the nitrogen of said amides includes one or more C 1-6 alkyl groups optionally substituted with N(R) 2 or 5–6 membered heterocyclic rings containing 1–2 heteroatoms; and wherein R is linear or branched C 1-12 aliphatic;
wherein R 3 is a group having a molecular weight up to 140 Daltons selected from aliphatic, aryl, aralkyl, heterocyclyl or heterocyclylalkyl ring wherein said heterocyclyl ring is a three to nine membered saturated or unsaturated mono-, bi-, or tri-heterocyclic ring system wherein each ring contains up to three heteroatoms selected from O, N, or S; and
wherein R 4 and R 5 taken together with the intervening nitrogen form a mono-, bi- or tricyclic hetero ring system wherein each ring of the system has 5–7 ring atoms;
wherein said ring system is optionally substituted with one or more groups independently selected from halogen, —R 9 , —OR 9 , —OH, —SH, —SR 9 , protected OH (such as acyloxy), phenyl (Ph), substituted Ph, —OPh, substituted —OPh, —NO 2 , —CN, —NH 2 , —NHR 9 , —N(R 9 ) 2 , —NHCOR 9 , —NHCONHR 9 , —NHCON(R 9 ) 2 , —NR 9 COR 9 , —NHCO 2 R 9 , —CO 2 R 9 , —CO 2 H, —COR 9 , —CONHR 9 , —CON(R 9 ) 2 , —S(O) 2 R 9 , —SONH 2 , —S(O)R 9 , —SO 2 NHR 9 , or —NHS(O) 2 R 9 ; and
wherein each R 9 is independently selected from an aliphatic group or a substituted aliphatic group.
26. The compound according to claim 1 wherein Z is oxygen;
wherein R 2 is:
CO 2 H, CH 2 CO 2 H or C 1-6 alkyl esters, C 3-10 cycloalkyl esters, or cholesterol esters thereof; or primary, secondary or tertiary amides thereof; wherein suitable substituents on the nitrogen of said amides includes one or more C 1-6 alkyl groups optionally substituted with N(R) 2 or 5–6 membered heterocyclic rings containing 1–2 heteroatoms; and wherein R is linear or branched C 1-12 aliphatic; and
wherein R 3 is a group having a molecular weight up to 140 Daltons selected from aliphatic, aryl, aralkyl, heterocyclyl or heterocyclylalkyl ring wherein said heterocyclyl ring is a three to nine membered saturated or unsaturated mono-, bi-, or tri-heterocyclic ring system wherein each ring contains up to three heteroatoms selected from O, N, or S.
27. The compound according to claim 1 wherein Z is oxygen;
wherein R 2 is:
CO 2 H, CH 2 CO 2 H or C 1-6 alkyl esters, C 3-10 cycloalkyl esters, or cholesterol esters thereof; or primary, secondary or tertiary amides thereof; wherein suitable substituents on the nitrogen of said amides includes one or more C 1-6 alkyl groups optionally substituted with N(R) 2 or 5–6 membered heterocyclic rings containing 1–2 heteroatoms; and wherein R is linear or branched C 1-12 aliphatic; and
wherein R 4 and R 5 taken together with the intervening nitrogen form a mono-, bi- or tricyclic hetero ring system wherein each ring of the system has 5–7 ring atoms;
wherein said ring system is optionally substituted with one or more groups independently selected from halogen, —R 9 , —OR 9 , —OH, —SH, —SR 9 , protected OH (such as acyloxy), phenyl (Ph), substituted Ph, —OPh, substituted —OPh, —NO 2 , —CN, —NH 2 , —NHR 9 , —N(R 9 ) 2 , —NHCOR 9 , —NHCONHR 9 , —NHCON(R 9 ) 2 , —NR 9 COR 9 , —NHCO 2 R 9 , —CO 2 R 9 , —CO 2 H, —COR 9 , —CONHR 9 , —CON(R 9 ) 2 , —S(O) 2 R 9 , —SONH 2 , —S(O)R 9 , —SO 2 NHR 9 , or —NHS(O) 2 R 9 ; and
wherein each R 9 is independently selected from an aliphatic group or a substituted aliphatic group.
28. The compound according to claim 1 wherein Z is oxygen;
wherein R 3 is a group having a molecular weight up to 140 Daltons selected from aliphatic, aryl, aralkyl, heterocyclyl or heterocyclylalkyl ring wherein said heterocyclyl ring is a three to nine membered saturated or unsaturated mono-, bi-, or tri-heterocyclic ring system wherein each ring contains up to three heteroatoms selected from O, N, or S; and
wherein R 4 and R 5 taken together with the intervening nitrogen form a mono-, bi- or tricyclic hetero ring system wherein each ring of the system has 5–7 ring atoms;
wherein said ring system is optionally substituted with one or more groups independently selected from halogen, —R 9 , —OR 9 , —OH, —SH, —SR 9 , protected OH (such as acyloxy), phenyl (Ph), substituted Ph, —OPh, substituted —OPh, —NO 2 , —CN, —NH 2 , —NHR 9 , —N(R 9 ) 2 , —NHCOR 9 , —NHCONHR 9 , —NHCON(R 9 ) 2 , —NR 9 COR 9 , —NHCO 2 R 9 , —CO 2 R 9 , —CO 2 H, —COR 9 , —CONHR 9 , —CON(R 9 ) 2 , —S(O) 2 R 9 , —SONH 2 , —S(O)R 9 , —SO 2 NHR 9 ,or —NHS(O) 2 R 9 ; and
wherein each R 9 is independently selected from an aliphatic group or a substituted aliphatic group.
29. The compound according to claim 1 wherein Z is oxygen;
wherein R 1 is hydrogen, —R, —CH 2 OR, —CH 2 SR, or —CH 2 Y; wherein R 2 is:
CO 2 H, CH 2 CO 2 H or C 1-6 alkyl esters, C 3-10 cycloalkyl esters, or cholesterol esters thereof; or primary, secondary or tertiary amides thereof; wherein suitable substituents on the nitrogen of said amides includes one or more C 1-6 alkyl groups optionally substituted with N(R) 2 or 5–6 membered heterocyclic rings containing 1–2 heteroatoms; and wherein R is linear or branched C 1-12 aliphatic; and
wherein R 3 is a group having a molecular weight up to 140 Daltons selected from aliphatic, aryl, aralkyl, heterocyclyl or heterocyclylalkyl ring wherein said heterocyclyl ring is a three to nine membered saturated or unsaturated mono-, bi-, or tri-heterocyclic ring system wherein each ring contains up to three heteroatoms selected from O, N, or S.
30. The compound according to claim 1 wherein Z is oxygen;
wherein R 1 is hydrogen, —R, —CH 2 OR, —CH 2 SR, or —CH 2 Y; wherein R 2 is:
CO 2 H, CH 2 CO 2 H or C 1-6 alkyl esters, C 3-10 cycloalkyl esters, or cholesterol esters thereof; or primary, secondary or tertiary amides thereof; wherein suitable substituents on the nitrogen of said amides includes one or more C 1-6 alkyl groups optionally substituted with N(R) 2 or 5–6 membered heterocyclic rings containing 1–2 heteroatoms; and wherein R is linear or branched C 1-12 aliphatic; and
wherein R 4 and R 5 taken together with the intervening nitrogen form a mono-, bi- or tricyclic hetero ring system wherein each ring of the system has 5–7 ring atoms;
wherein said ring system is optionally substituted with one or more groups independently selected from halogen, —R 9 , —OR 9 , —OH, —SH, —SR 9 , protected OH (such as acyloxy), phenyl (Ph), substituted Ph, —OPh, substituted —OPh, —NO 2 , —CN, —NH 2 , —NHR 9 , —N(R 9 ) 2 , —NHCOR 9 , —NHCONHR 9 , —NHCON(R 9 ) 2 , —NR 9 COR 9 , —NHCO 2 R 9 , —CO 2 R 9 , —CO 2 H, —COR 9 , —CONHR 9 , —CON(R 9 ) 2 , —S(O) 2 R 9 , —SONH 2 , —S(O)R 9 , —SO 2 NHR 9 , or —NHS(O) 2 R 9 ; and
wherein each R 9 is independently selected from an aliphatic group or a substituted aliphatic group.
31. The compound according to claim 1 wherein Z is oxygen;
wherein R 1 is hydrogen, —R, —CH 2 OR, —CH 2 SR, or —CH 2 Y; wherein R 3 is a group having a molecular weight up to 140 Daltons selected from aliphatic, aryl, aralkyl, heterocyclyl or heterocyclylalkyl ring wherein said heterocyclyl ring is a three to nine meinbered saturated or unsaturated mono-, bi-, or tri-heterocyclic ring system wherein each ring contains up to three heteroatoms selected from O, N, or S; and
wherein R 4 and R 5 taken together with the intervening nitrogen form a mono-, bi- or tricyclic hetero ring system wherein each ring of the system has 5–7 ring atoms;
wherein said ring system is optionally substituted with one or more groups independently selected from halogen, —R 9 , —OR 9 , —OH, —SH, —SR 9 , protected OH (such as acyloxy), phenyl (Ph), substituted Ph, —OPh, substituted —OPh, —NO 2 , —CN, —NH 2 , —NHR 9 , —N(R 9 ) 2 , —NHCOR 9 , —NHCONHR 9 , —NHCON(R 9 ) 2 , —NR 9 COR 9 , —NHCO 2 R 9 , —CO 2 R 9 , —CO 2 H, —COR 9 , —CONHR 9 , —CON(R 9 ) 2 , —S(O) 2 R 9 , —SONH 2 , —S(O)R 9 , —SO 2 NHR 9 , or —NHS(O) 2 R 9 ; and
wherein each R 9 is independently selected from an aliphatic group or a substituted aliphatic group.
32. The compound according to claim 1 wherein Z is oxygen;
wherein R 2 is:
CO 2 H, CH 2 CO 2 H or C 1-6 alkyl esters, C 3-10 cycloalkyl esters, or cholesterol esters thereof; or primary, secondary or tertiary amides thereof; wherein suitable substituents on the nitrogen of said amides includes one or more C 1-6 alkyl groups optionally substituted with N(R) 2 or 5–6 membered heterocyclic rings containing 1–2 heteroatoms; and wherein R is linear or branched C 1-12 aliphatic;
wherein R 3 is a group having a molecular weight up to 140 Daltons selected from aliphatic, aryl, aralkyl, heterocyclyl or heterocyclylalkyl ring wherein said heterocyclyl ring is a three to nine membered saturated or unsaturated mono-, bi-, or tri-heterocyclic ring system wherein each ring contains up to three heteroatoms selected from O, N, or S; and
wherein R 4 and R 5 taken together with the intervening nitrogen form a mono-, bi- or tricyclic hetero ring system wherein each ring of the system has 5–7 ring atoms;
wherein said ring system is optionally substituted with one or more groups independently selected from halogen, —R 9 , —OR 9 , —OH, —SH, —SR 9 , protected OH (such as acyloxy), phenyl (Ph), substituted Ph, —OPh, substituted —OPh, —NO 2 , —CN, —NH 2 , —NHR 9 , —N(R 9 ) 2 , —NHCOR 9 , —NHCONHR 9 , —NHCON(R 9 ) 2 , —NR 9 COR 9 , —NHCO 2 R 9 , —CO 2 R 9 , —CO 2 H, —COR 9 , —CONHR 9 , —CON(R 9 ) 2 , —S(O) 2 R 9 , —SONH 2 , —S(O)R 9 , —SO 2 NHR 9 , or —NHS(O) 2 R 9 ; and
wherein each R 9 is independently selected from an aliphatic group or a substituted aliphatic group.
33. The compound according to claim 1 wherein R 1 is hydrogen, —R, —CH 2 OR, —CH 2 SR, or —CH 2 Y;
wherein R 2 is:
CO 2 H, CH 2 CO 2 H or C 1-6 alkyl esters, C 3-10 cycloalkyl esters, or cholesterol esters thereof; or primary, secondary or tertiary amides thereof; wherein suitable substituents on the nitrogen of said amides includes one or more C 1-6 alkyl groups optionally substituted with N(R) 2 or 5–6 membered heterocyclic rings containing 1–2 heteroatoms; and wherein R is linear or branched C 1-12 aliphatic;
wherein R 3 is a group having a molecular weight up to 140 Daltons selected from aliphatic, aryl, aralkyl, heterocyclyl or heterocyclylalkyl ring wherein said heterocyclyl ring is a three to nine membered saturated or unsaturated mono-, bi-, or tri-heterocyclic ring system wherein each ring contains up to three heteroatoms selected from O, N, or S; and
wherein R 4 and R 5 taken together with the intervening nitrogen form a mono-, bi- or tricyclic hetero ring system wherein each ring of the system has 5–7 ring atoms;
wherein said ring system is optionally substituted with one or more groups independently selected from halogen, —R 9 , —OR 9 , —OH, —SH, —SR 9 , protected OH (such as acyloxy), phenyl (Ph), substituted Ph, —OPh, substituted —OPh, —NO 2 , —CN, —NH 2 , —NHR 9 , —N(R 9 ) 2 , —NHCOR 9 , —NHCONHR 9 , —NHCON(R 9 ) 2 , —NR 9 COR 9 , —NHCO 2 R 9 , —CO 2 R 9 , —CO 2 H, —COR 9 , —CONHR 9 , —CON(R 9 ) 2 , —S(O) 2 R 9 , —SONH 2 , —S(O)R 9 , —SO 2 NHR 9 , or —NHS(O) 2 R 9 ; and
wherein each R 9 is independently selected from an aliphatic group or a substituted aliphatic group.
34. The compound according to claim 1 wherein Z is oxygen;
wherein R 1 is hydrogen, —R, —CH 2 OR, —CH 2 SR, or —CH 2 Y; wherein R 2 is:
CO 2 H, CH 2 CO 2 H or C 1-6 alkyl esters, C 3-10 cycloalkyl esters, or cholesterol esters thereof; or primary, secondary or tertiary amides thereof; wherein suitable substituents on the nitrogen of said amides includes one or more C 1-6 alkyl groups optionally substituted with N(R) 2 or 5–6 membered heterocyclic rings containing 1–2 heteroatoms; and wherein R is linear or branched C 1-12 aliphatic;
wherein R 3 is a group having a molecular weight up to 140 Daltons selected from aliphatic, aryl, aralkyl, heterocyclyl or heterocyclylalkyl ring wherein said heterocyclyl ring is a three to nine membered saturated or unsaturated mono-, bi-, or tri-heterocyclic ring system wherein each ring contains up to three heteroatoms selected from O, N, or S; and
wherein R 4 and R 5 taken together with the intervening nitrogen form a mono-, bi- or tricyclic hetero ring system wherein each ring of the system has 5–7 ring atoms;
wherein said ring system is optionally substituted with one or more groups independently selected from halogen, —R 9 , —OR 9 , —OH, —SH, —SR 9 , protected OH (such as acyloxy), phenyl (Ph), substituted Ph, —OPh, substituted —OPh, —NO 2 , —CN, —NH 2 , —NHR 9 , —N(R 9 ) 2 , —NHCOR 9 , —NHCONHR 9 , —NHCON(R 9 ) 2 , —NR 9 COR 9 , —NHCO 2 R 9 , —CO 2 R 9 , —CO 2 H, —COR 9 , —CONHR 9 , —CON(R 9 ) 2 , —S(O) 2 R 9 , —SONH 2 , —S(O)R 9 , —SO 2 NHR 9 , or —NHS(O) 2 R 9 ; and
wherein each R 9 is independently selected from an aliphatic group or a substituted aliphatic group.
35. The compound according to claim 1 wherein R 2 is CO 2 H.
36. The compound according to claim 1 wherein R 1 is —CH 2 OR, —CH 2 SR, or —CH 2 Y.
37. The compound according to claim 36 wherein R 1 is —CH 2 Y.
38. The compound according to claim 36 wherein R 1 is —CH 2 F.
39. The compound according to claim 1 wherein R 3 is a C 1-4 alkyl group.
40. The compound according to claim 1 wherein R 1 is —CH 2 F and R 3 is a C 1-4 alkyl group.
41. The compound according to claim 1 wherein R 4 and R 5 taken together with the intervening nitrogen form a ring selected from isoindole, indoline, indazole, purine, dihydropyridine, benzimidazole, imidazole, imidazoline, pyrrole, pyrrolidine, pyrroline, pyrazole, pyrazoline, pyrazolidine, triazole, piperidine, morpholine, thiomorpholine, piperazine, phenothiazine, phenoxazine, dihydrophenazine, dihydrocinnoline, dihydroquinoxaline, tetrahydroquinoline, tetrahydroisoquinoline, dibenzoazepine, dihydro-dibenzoazepine, dihydronaphthyridine, tetrahydronaphthyridine, dihydroacridine, β-carboline, pyrido[4,3-b]indole, 2,3,9-triazafluorene, 9-thia-2,10-diazaanthracene, 3,6,9-triazafluorene, thieno[3,2-b]pyrrole, or dihydrophenanthridine;
wherein said ring is optionally substituted with one or more groups independently selected from halogen, —R 9 , —OR 9 , —OH, —SH, —SR 9 , protected OH (such as acyloxy), phenyl (Ph), substituted Ph, —OPh, substituted —OPh, —NO 2 , —CN, —NH 2 , —NHR 9 , —N(R 9 ) 2 , —NHCOR 9 , —NHCONHR 9 , —NHCON(R 9 ) 2 , —NR 9 COR 9 , —NHCO 2 R 9 , —CO 2 R 9 , —CO 2 H, —COR 9 , —CONHR 9 , —CON(R 9 ) 2 , —S(O) 2 R 9 , —SONH 2 , —S(O)R 9 , —SO 2 NHR 9 , or —NHS(O) 2 R 9 ; and
wherein each R 9 is independently selected from an aliphatic group or a substituted aliphatic group.
42. The compound according to claim 41 wherein R 4 and R 5 taken together with the intervening nitrogen form a ring selected from carbazole, phenothiazine, indole, indoline, 5H-dibenzo[b,f]azepine, 10,11-dihydro-5H-dibenzo[b,f]azepine, β-carboline, pyridol[4,3-b]indole, 2,3,9-triazafluorene, 9-thia-2,10-diazaanthracene, 3,6,9-triazafluorene, thieno[3,2-b]pyrrole, or dihydrophenanthridine;
wherein said ring is optionally substituted with one or more groups independently selected from halogen, —R 9 , —OR 9 , —OH, —SH, —SR 9 , protected OH (such as acyloxy), phenyl (Ph), substituted Ph, —OPh, substituted —OPh, —NO 2 , —CN, —NH 2 , —NHR 9 , —N(R 9 ) 2 , —NHCOR 9 , —NHCONHR 9 , —NHCON(R 9 ) 2 , —NR 9 COR 9 , —NHCO 2 R 9 , —CO 2 R 9 , —CO 2 H, —COR 9 , —CONHR 9 , —CON(R 9 ) 2 , —S(O) 2 R 9 , —SONH 2 , —S(O)R 9 , —SO 2 NHR 9 , or —NHS(O) 2 R 9 ; and
wherein each R 9 is independently selected from an aliphatic group or a substituted aliphatic group.
43. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
44. A method of treating a caspase-mediated disease selected from osteoarthritis, rheumatoid arthritis or psoriasis, in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound according to formula I:
wherein:
Z is oxygen or sulfur;
R 1 is hydrogen, —CNN 2 , —R, —CH 2 OR, —CH 2 SR, or —CH 2 Y;
R is a C 1-12 aliphatic, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl ring, wherein each of these groups is optionally substituted, and wherein said heterocyclic ring is a three to nine membered saturated or unsaturated mono-, bi-, or tri-heterocyclic ring system wherein each ring contains up to three heteroatoms selected from O, N, or S;
Y is an electronegative leaving group selected from F, Cl, Br, I, arylsulfonyloxy, alkylsulfonyloxy, trifluoromethanesulfonyloxy, OR′, SR′, —OC═O(R′), or —OPO(R 6 ) (R 7 );
wherein R′is an aliphatic group, an aryl group, an aralkyl group, a carbocyclic group, an alkyl carbocyclic group, a heterocyclic group, or an alkyl heterocyclic group;
wherein R 6 and R 7 are independently selected from R or OR;
R 2 is CO 2 H, CH 2 CO 2 H or C 1-6 alkyl esters, C 3-10 cycloalkyl esters, or cholesterol esters thereof; or primary, secondary or tertiary amides thereof; wherein suitable substituents on the nitrogen of said amides includes one or more C 1-6 alkyl groups optionally substituted with N(R) 2 or 5–6 membered heterocyclic rings containing 1–2 heteroatoms; and wherein R is linear or branched C 1-12 aliphatic;
R 3 is selected from H, a side chain of a natural α-amino acid, or a substituted or unsubstituted group having a molecular weight up to about 140 Daltons selected from aliphatic, aryl, aralkyl, heterocyclyl or heterocyclylalkyl ring wherein said heterocyclyl or heterocyclylalkyl ring is a three to nine membered saturated or unsaturated mono-, bi-, or tri-heterocyclic ring system wherein each ring contains up to three heteroatoms selected from O, N, or S; and
R 4 and R 5 taken together with the intervening nitrogen form a mono-, bi- or tricyclic hetero ring system having 1–6 heteroatoms selected from nitrogen, oxygen or sulfur;
wherein said ring system is optionally substituted with one or more groups independently selected from halogen, —R 9 , —OR 9 , —OH, —SH, —SR 9 , protected OH (such as acyloxy), phenyl (Ph), substituted Ph, —OPh, substituted —OPh, —NO 2 , —CN, —NH 2 , —NHR 9 , —N(R 9 ) 2 , —NHCOR 9 , —NHCONHR 9 , —NHCON(R 9 ) 2 , —NR 9 COR 9 , —NHCO 2 R 9 , —CO 2 R 9 , —CO 2 H, —COR 9 , —CONHR 9 , —CON(R 9 ) 2 , —S(O) 2 R 9 , —SONH 2 , —S(O)R 9 , —SO 2 NHR 9 , or —NHS(O) 2 R 9 ;
wherein each R 9 is independently selected from an
aliphatic group or a substituted aliphatic group;
wherein the optional substituents on said C 1-12 aliphatic group or aryl, aralkyl, heterocyclyl, or heterocyclylalkyl ring is independently selected from, from halogen, —R 11 , —OR 11 , —OH, —SH, —SR 11 , acyloxy, substituted or unsubstituted Ph or OPh, —NO 2 , —CN, —NH 2 , —NHR 11 , —N(R 11 ) 2 , —NHCOR 11 , —NHCONHR 11 , —NHCON(R 11 ) 2 , —NR 11 COR 11 , —NHCO 2 R 11 , —CO 2 R 11 , —CO 2 H, —COR 11 , —CONHR 11 , —CON(R 11 ) 2 , —S(O) 2 R 11 , —SONH 2 , —S(O)R 11 , —SO 2 NHR 11 , —NHS(O) 2 R 11 , ═O, ═S, ═NNHR 11 , ═NNR 11 2 , ═N—OR 11 , ═NNHCOR 11 , ═NNHCO 2 R 11 , ═NNHSO 2 R 11 , or ═NR 11 ; and
wherein each R 11 is independently selected from a C 1-12 aliphatic group or a substituted C 1-12 aliphatic group.
45. A method for the preservation of cells in an organ for transplant or in a blood product said method comprising the step of bathing the cells in a solution of a compound according to claim 1 .Cited by (0)
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